Hormonal Contraception and Endometrial Thickness in IVF/ICSI Cycles: A Multicentre Historical Cohort Study

Michaelsen MP; Nielsen LC; Poulsen M; Skals RG; Troest B; Bentzen JG; Elers J; Gabrielsen AV; Grøndahl ML; Povlsen BB; Tang-Pedersen M; Kesmodel US

doi:10.1111/1471-0528.18295

Diagnostics · Endometrial Assessment

Hormonal Contraception and Endometrial Thickness in IVF/ICSI Cycles: A Multicentre Historical Cohort Study

Michaelsen MP, Nielsen LC, Poulsen M, Skals RG, Troest B, Bentzen JG, Elers J, Gabrielsen AV, Grøndahl ML, Povlsen BB, Tang-Pedersen M, Kesmodel US

BJOG: An International Journal of Obstetrics and Gynaecology, 2025

DOI 10.1111/1471-0528.18295 PMID 40665779 PMC PMC12411652

Read our synopsis

RRM Academy Synopsis

Past levonorgestrel IUD use linked to thinner lining in IVF cycles

In this Danish cohort, previous levonorgestrel intrauterine system (LNG-IUS) use was associated with a thinner endometrium in women having IVF/ICSI. The register-based study covered 12 786 women and 22 464 cycles. A lining under 7 mm appeared in about 15 out of 100 LNG-IUS cycles. It appeared in about 5 out of 100 no/other contraception cycles.

Key Findings

A lining under 7 mm appeared in 14.5% of LNG-IUS group cycles, the highest share, and in 4.8% of no/other contraception cycles, the lowest.
Relative to LNG-IUS, odds of a lining of ≥ 7 mm were higher after combined oral contraceptive pills (OR 3.53, 95% CI 1.29–9.65) and progestogen-only pills (OR 6.43, 95% CI 1.45–28.63).
Relative to LNG-IUS, no/other contraception had higher odds of a lining of ≥ 7 mm (OR 6.67, 95% CI 2.37–18.74).
After adjustment, every duration of LNG-IUS use (0–3, > 3–6, > 6–9 and > 9 years) had lower odds of a lining of ≥ 7 mm than no/other contraception.
Clinical pregnancy showed no statistically significant difference between LNG-IUS and other methods, or across LNG-IUS durations, in completed cycles that reached embryo transfer.

Interpretation

An observational register cohort can show association. The LNG-IUS-only group held just 76 cycles, against 14 535 for oral contraceptive pills, and the method comparisons had wide intervals. Analyses of each woman's first cycle were directionally consistent with the main results, but the LNG-IUS comparisons with other methods were non-significant. Every participant was in IVF/ICSI treatment. The authors could not adjust for genetics or reproductive history. They call the results likely hypothesis-generating and say the clinical relevance of the 7 mm threshold remains uncertain.

RRM Context

The authors describe the LNG-IUS as causing atrophy of the endometrium. Restorative Reproductive Medicine (RRM) works with the ovulatory cycle, and suppressive medications sit on the other side of that principle. The authors say the biological basis of any lasting effect on the lining is yet to be established. The paper has no data on women outside IVF/ICSI treatment.

Our editorial summary of this paper, not the article's abstract.

Abstract

Objective

To study the association between previous use of levonorgestrel intrauterine system (LNG-IUS) and endometrial thickness (EMT) in women undergoing in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles.

Design

Multicentre historical cohort study.

Setting

Eight Danish public and private fertility clinics.

Population

12786 women aged 18-46 years contributing with an EMT measurement from 22 464 different IVF/ICSI treatment cycles between 2000 and 2021.

Methods

Exposure was previous use of LNG-IUS, combined oral contraceptive pills (OCPs), progestogen-only pills (POPs), no/other contraception or combined, cumulated use of contraception when more contraceptives had been used during the inclusion period. LNG-IUS use was categorised into 0-3 years, >3-6 years, >6-9 years and >9 years. Mixed effect logistic regression adjusted for age, BMI, smoking, educational level, total FSH dose and fertility clinic was used.

Main Outcome Measures

EMT (< 7 mm vs >= 7 mm).

Results

Statistically significantly higher odds of EMT >= 7 mm were found for OCPs [OR 3.53 (95% CI 1.29-9.65)], POPs [OR 6.43 (95% CI 1.45-28.63)] and no/other contraception [OR 6.67 (95% CI 2.37-18.74)] relative to LNG-IUS in IVF/ICSI cycles. All duration categories of ever use of LNG-IUS were associated with significantly lower odds of EMT >= 7 mm compared to no/other contraception.

Conclusions

Previous use of LNG-IUS was associated with decreased endometrial growth in women undergoing IVF/ICSI.

Topics

By this author

Ovulation Agents · Selective Estrogen Receptor Modulators

Fertility treatment with clomiphene citrate and childhood epilepsy: a nationwide cohort study

Kettner LO et al., 2021 Human reproduction (Oxford, England)

Is fertility treatment with clomiphene citrate associated with an increased risk of childhood epilepsy, including specific subtypes of epilepsy? Fertility treatment with clomiphene citrate may be associated with a small increased risk of idiopathic generalized epilepsy and focal epilepsy in childhood. Clomiphene citrate is among the most commonly prescribed drugs for fertility treatment. However, concerns have been raised as to whether the treatment may harm the developing fetus. This nationwide cohort study included all pregnancies in Denmark from 1 July 1995 resulting in a live-born singleton child before 31 December 2013. The children were followed until 31 December 2016. Children conceived after fertility treatment with clomiphene citrate were identified from the Danish National Prescription Registry. The primary outcomes were childhood epilepsy, idiopathic generalized epilepsy, and focal epilepsy identified from the Danish National Patient Register and from antiepileptic drug prescriptions in the Danish National Prescription Registry. All analyses were conducted using Cox proportional hazards regression. A total of 1 081 291 pregnancies were included; 12 644 children (1.2%) developed epilepsy. Fertility treatment with clomiphene citrate was associated with a small increased risk of childhood epilepsy (hazard ratio [HR]: 1.10; 95% CI: 1.00-1.22), idiopathic generalized epilepsy (HR: 1.41; 95% CI: 1.16-1.72), and focal epilepsy (HR: 1.26; 95% CI: 1.04-1.53). The increased risk of idiopathic generalized epilepsy may be due to confounding from time stable parental characteristics related to treatment with clomiphene citrate, since the association was strongest with the lowest administered dosage of clomiphene citrate prior to conception, and the association disappeared in a sibling analysis. The increased risk of focal epilepsy may be related to the hormonal treatment, since the association tended to increase with increasing cumulative dosage of clomiphene citrate prior to conception, and the association persisted in a sibling analysis. This finding may be of clinical importance, since alternative hormones are available for fertility treatment. Financial support from Aarhus University and the Aase and Ejnar Danielsen Foundation. U.S.K. received personal teaching fees from Merck, outside the submitted work. N/A.

Safety and Risks · Neonatal and Birth Outcomes

Risk of stillbirth in low-risk singleton term pregnancies following fertility treatment: a national cohort study

Bay B et al., 2019 BJOG : an international journal of obstetrics and gynaecology

To assess the risk of stillbirth in low-risk in vitro fertilisation (IVF) pregnancies. Register-based national cohort study. Denmark 2003-2013. Cohort of 425 732 singleton pregnancies including 10 235 conceived following IVF/intracytoplasmic sperm injection (ICSI), 4521 conceived following intrauterine insemination (IUI), and 410 976 spontaneously conceived. Information on pregnancy, obstetrical risk factors, stillbirth, and fertility treatment was obtained from the Danish national health registers for all pregnancies after gestational week 21+6 . We estimated the overall and gestational age-specific risk of stillbirth in low-risk term pregnancies following IVF, ICSI, and IUI. Further, we estimated the association between stillbirth and IVF and ICSI respectively as well as fresh or frozen-thawed embryo transfer. Risk of stillbirth. The number of stillbirths in spontaneously conceived and IVF/ICSI low-risk term pregnancies was 525 (0.1%) and 35 (0.3%), respectively. In multivariate analysis, the risk of stillbirth in pregnancies following IVF/ICSI was increased (odds ratio 2.1, 95% CI 1.4-3.1). The risk of stillbirth was correspondingly increased in time-to-event analyses taking risk time for each fetus into account from gestational week 37 and onwards (hazard ratio 2.4, 95% CI 1.6-3.6). In sub-analyses, the risk of stillbirth was increased for pregnancies following ICSI (odds ratio 2.2, 95% CI 1.2-3.1), but not IVF (odds ratio 1.7, 95% CI 0.9-3.1). We found a systematically increased risk of stillbirth in low-risk term pregnancies following IVF/ICSI. Whether the risk was related to the treatment or to underlying subfertility is uncertain. The results may indicate a need for obstetrical surveillance for these pregnancies when reaching term. Increased risk of stillbirth in low-risk term pregnancies following fresh cycle IVF/ICSI.

Related research

Oral Contraceptives · Cancer Risk

Effect of long-term combined oral contraceptive pill use on endometrial thickness

Talukdar N et al., 2012 Obstetrics and gynecology

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Long Acting Methods · Intrauterine Devices

Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies

Apter D et al., 2014 Fertility and sterility

To assess the pharmacokinetics and pharmacodynamics of levonorgestrel intrauterine system (LNG-IUS) 13.5 mg and LNG-IUS 19.5 mg (total content). Pooled pharmacokinetic and pharmacodynamic analyses of phase II and III studies. Randomized, open-label, multicenter studies. PATIENT(S): Nulliparous and parous women. INTERVENTION(S): Levonorgestrel intrauterine system 13.5 mg, LNG-IUS 19.5 mg, or LNG-IUS 20 μg/24 h (total content 52 mg). MAIN OUTCOME MEASURE(S): Pharmacokinetics of LNG, ovulation rate, cervical function, and endometrium effects. RESULT(S): The in vivo LNG release rate of LNG-IUS 13.5 mg was approximately 14 μg/24 h after 24 days, declining progressively to 5 μg/24 h after 3 years. The average LNG serum concentration over 3 years of use was 74.3 ng/L, 114 ng/L, and 218 ng/L for LNG-IUS 13.5 mg, LNG-IUS 19.5 mg, and LNG-IUS 20 μg/24 h, respectively. All treatments showed very similar progestogenic effects on cervical mucus, with low and similar cervical scores throughout treatment. Ovulation was observed in the majority of women in all groups where assessment was possible, although there was a lower incidence of anovulation with LNG-IUS 13.5 mg and LNG-IUS 19.5 mg compared with LNG-IUS 20 μg/24 h. The progestogenic effect on the endometrium was marked in all three LNG-IUS groups. CONCLUSION(S): Levonorgestrel intrauterine system 13.5 mg and LNG-IUS 19.5 mg result in alower systemic exposure to LNG, lower incidence of anovulation, and similar progestin impact on the endometrium and cervical function compared with LNG-IUS 20 μg/24 h.

Long Acting Methods · Intrauterine Devices

The 13.5-mg, 19.5-mg, and 52-mg Levonorgestrel-Releasing Intrauterine Systems and Risk of Ectopic Pregnancy

Elgemark K et al., 2022 Obstetrics and gynecology

To assess the Pearl Index for risk of ectopic pregnancy in women using levonorgestrel-releasing intrauterine systems (LNG-IUS) with hormonal reservoirs of 13.5 mg, 19.5 mg, or 52 mg. This was a retrospective cohort study. Women diagnosed with an ectopic pregnancy in Stockholm County, Sweden, between January 1, 2014, and December 31, 2019, were identified through the electronic medical record system. The final analysis included 2,252 cases of ectopic pregnancy. Information on age, reproductive and medical history, as well as current use of contraception was retrieved. The time of intrauterine device (IUD) insertion before ectopic pregnancy and the numbers of sold LNG-IUS during the study period were used to calculate the incidence rate for ectopic pregnancy during use per 100 woman-years (Pearl Index). Among women with an ectopic pregnancy diagnosis, 105 presented with a known type of hormonal IUD in situ, of whom 94 were included in the calculations of the Pearl Index. The estimated Pearl Index for ectopic pregnancy was 0.136 (95% CI 0.106-0.176) for the LNG-IUS 13.5-mg, 0.037 (95% CI 0.021-0.067) for the LNG-IUS 19.5-mg, and 0.009 (95% CI 0.006-0.014) for the LNG-IUS 52-mg. With the 52-mg LNG-IUS as referent, the relative risk (RR) for ectopic pregnancy was higher during the first year for LNG 13.5-mg (RR 20.59, 95% CI 12.04-35.21), and for both 13.5-mg (RR 14.49, 95% CI 9.01-23.3) and 19.5-mg (RR 4.44, 95% CI 1.64-12.00) during the total study period. The absolute risk of ectopic pregnancy during the use of LNG-IUS at any doses was low. The results show that the lower the dose of the IUD, the higher the risk of an ectopic pregnancy. Higher-dose LNG-IUS should be considered when providing contraceptive counseling to a woman with known risk factors for ectopic pregnancy who are considering a hormonal IUD.

Ovulation Agents · Selective Estrogen Receptor Modulators

A randomized prospective study comparing pregnancy rates after clomiphene citrate and human menopausal gonadotropin before intrauterine insemination

Ecochard R et al., 2000 Fertility and sterility

To determine whether hMG offers an advantage over clomiphene citrate (CC) in achieving pregnancy after IUI with husband's sperm. Randomized prospective trial. Infertility patients in a university teaching hospital. PATIENT(S): Fifty-eight women under 39 years old undergoing ovulation induction before IUI. INTERVENTION(S): The women were assigned randomly to one of two treatment groups. Patients in group I (CCHH) received CC for the first two cycles and hMG for the last two cycles. Patients in group II (HHCC) received hMG for the first two cycles and CC for the last two cycles. MAIN OUTCOME MEASURE(S): Cycle fecundity rates for the two treatment modalities were compared statistically with use of life-table analysis. RESULT(S): Of the 174 cycles studied, overall cycle fecundity rate was 11.11 (9 of 81 cycles) in the CCHH group and 10.75 (10 of 93 cycles) in the HHCC group. The difference was not statistically significant. The cycle fecundity rate was 14.44% (13 of 90 cycles) for cycles with CC and 7.14% (6 of 84) with hMG. The difference was not statistically significant. CONCLUSION(S): These data suggest that CC is an effective alternative to hMG in the population examined.

Diagnostics › Endometrial Assessment › Luteal Phase Biopsy · Contraception › Long Acting Methods › Intrauterine Devices · Assisted Reproduction › Outcomes and Effectiveness › Outcomes by Diagnosis

PMID 40665779 40665779 DOI 10.1111/1471-0528.18295 10.1111/1471-0528.18295 Michaelsen et al. 2025, Michaelsen 2025

Cite this article

Michaelsen, M. P., Nielsen, L. C., Poulsen, M., Skals, R. G., Troest, B., Bentzen, J. G., Elers, J., Gabrielsen, A. V., Grøndahl, M. L., Povlsen, B. B., Tang-Pedersen, M., & Kesmodel, U. S. (2025). Hormonal Contraception and Endometrial Thickness in IVF/ICSI Cycles: A Multicentre Historical Cohort Study. BJOG: An International Journal of Obstetrics and Gynaecology. https://doi.org/10.1111/1471-0528.18295